DISCLAIMER: The cases / examples on this blog have been anonymised to maintain confidentiality of patients. Cases have been acquired from various international hospitals and through other medical colleagues with the intention to teach through case examples.

Tuesday, 24 June 2008

There is too much reliance on machinery to try and help us as physicians make a diagnosis.

The next case, which as always has been anonymised, demonstrates that a simple history and bedside examination was all that was needed to establish a firm diagnosis.

A 70 year old female was admitted to a hospital in North Japan with dizziness on standing, weakness of her legs and blurring of her vision.

She had been otherwise well one week before admission and had been started on hypertensive medication by a local doctor for newly diagnosed hypertension. The patient had been taking the drug according to directions. However, she began to experience dizziness on standing and leg weakness. All symptoms resolved when she was lying flat at night time. She denied collapse or loss of consciousness and there was no history of chest pain. However, when she stood up, she did experience a rapid heart beat but without chest discomfort.

There was no previous medical history of note.

She was a non-smoker and only drank occasional alcohol. She lived with her husband in a ground floor apartment.

On examination the patient looked well and was alert and fully conversant.

The resident was uncertain of the cause of the symptoms and the patient underwent several tests.

ECG- revealed slight sinusoidal T wave abnormalities in the lateral chest leads but there was no ST elevation or depression.

Lab Data- revealed elevated liver function with AST and ALT being 3x normal. The bilirubin and ALP were normal. All other blood results were normal including the CBC, Renal function and Cardiac enzymes (CK and Troponin-T).

CXR- was within normal limits.

CT head scan was performed which revealed only age-related cerebral atrophy.

MRI head scan again revealed no pathological problem.

In this case, the history is extremely important. The patient had started a new anti-hypertensive drug and had begun to develop what appeared to be postural-related symptoms which resolved on lying flat.

Unfortunately, the history had not been fully appreciated by the resident. Despite a normal neurological examination, the patient still underwent cranial scanning, twice, which was unnecessary.

An astute physician reviewed the patient at the bedside and obtained further history which again supported the likely diagnosis of postural hypotension. A simple bedside test was performed which gave the diagnosis.

Initially, the patient was laid flat and the blood pressure was 193/92mmHg. The patient was then elevated to about 50 degrees sitting and at one minute the blood pressure was rechecked and was 189/87mmHg and there were no symptoms. At two minutes with still no symptoms present, the blood pressure was 180/79mmHg. By three minutes, the patient was developing blurred vision and the blood pressure was 178/77mmHg. It was decided to stand the patient with her being held on either side by a physician and with a third physician checking the blood pressure. Full resuscitation equipment was available in case of collapse.

On standing, the patient developed the full set of dizziness symptoms but was fully conversant with no loss of consciousness. The blood pressure at one minute was 150/69mmHg. Pulse rate had not risen appreciably.

On lying the patient flat, the symptoms completely resolved.

Hence, this patient had confirmed postural (orthostatic) hypotension likely to be drug-induced.

A blood pressure drop of more than 20 mmHg of the systolic and / or 10 mmHg of the diastolic (20/10 mmHg) are consistent with the diagnosis of postural hypotension.

However, with such a strong history of starting a new drug and developing postural hypotension, the drug was the likely offender and in addition, it may well have been the cause of the mild liver dysfunction.

In this case, a simple bedside test would have sufficed to make the diagnosis. Cranial scanning was not necessary especially as the thorough neurological examination was within normal parameters.

You may be saying to yourself, 'Hang on a minute, the blood pressure is still high but the patient has hypotensive symptoms?!' Yes, that is correct. This patient despite not having what we would all regard as true hypotension nevertheless has a sufficient drop in both systolic and diastolic blood pressure on standing to cause symptoms. This is a relative hypotension and is still relevant and should not be ignored just because the systolic blood pressure remains above 100mmHg !

Normal Blood Pressure Homeostasis

When initially standing up, approximately 0.5-1.0 litres of venous blood pools in the capacitance vessels. Baroreceptors sense a drop in blood pressure and result in reflex vasoconstriction, increased heart rate and return of venous blood to the heart. These effects are immediate and without appreciable symptoms to a normal individual. Longer term changes include increased renin output to increase angiotensin II and aldosterone to increase vessel tone and sodium reabsorption respectively. Other changes include the increased output of ADH which leads to vasoconstriction and increased water absorption from the kidneys.

Pathological Causes

Hypovolaemia- in states of severe hypovolaemia e.g. bleeding, approximately 3o% of the blood volume can be lost before postural blood pressure drops can be seen. This is especially relevant in young patients. Hence, asking questions about bleeding and searching for possible unseen causes e.g. abrutio placenta, GI haemorrhage are mandatory.

Drugs- the elderly are very sensitive to drugs. Even seemingly innocuous drugs can have adverse side effects such thiazide diuretics, tricyclic antidepressants, beta-blockers, neuroleptic medications. As I always say, take a decent drug history and look up the side-effects (if you don't already know them) and check for drug-drug interactions!

Adrenal Failure- steroids are required to allow the vascular smooth muscle to be responsive to circulating catecholamines to maintain vascular tone. Hypocortisolaemia leads to vascular collapse and hence, patients with no obvious hypovolaemia and no offending drugs, should have this easily treatable condition ruled out. Other possible signs might be a low sodium and high potassium in addition to fasting hypoglycaemia. However, patients with a normal K level can still have hypocortisolaemia.

Pituitary Failure- Absence of ACTH leads to a similar problem of hypocortisolaemia. Whereas adrenal failure is associated with raised ACTH levels and hyperpigmentation, panhypopituitarism, and hence low ACTH output, is not. Checking anterior pituitary hormones would be advisable and should be part of the work-up for patients in whom the immediate cause of postural hypotension is not clear.

Other conditions are associated with autonomic failure and include diabetes mellitus, and hence, checking a fasting glucose and a 75 gram oral glucose tolerance test would be appropriate. HbA1c is not part of the British or American Diabetes Association guidelines for making the diagnosis of diabetes as it can be misleading.

Multi-System Atrophy (MSA) which includes the famous Shy-Drager and Parkinsonism etc should be considered but such abnormalities of cerebellar dysfunction, tremor, bradykinesia and cog-wheel rigidity should be unmasked during the physical examination (if performed correctly!)

Autonomic failure can be examined for by doing the postural blood pressure testing and checking compensatory changes in heart rate. If the heart rate fails to increase by more than 10 beats per minute during the postural test, then this suggests autonomic failure. Heart rate increase > 100 / min suggests hypovolaemia. If symptoms develop without hypotension, then this suggests Postural Orthostatic Tachycardia Syndrome (POTS); this is usually evident in younger patients.

Investigations for autonomic failure include the measuring of the R-R interval on ECG with the patient doing slow breathing. The ratio of the R-R interval of expiration to inspiration should be more than 1.15. If less, it suggests autonomic failure.

Postural manoeuvres such as getting out of bed slowly in the morning, taking sufficient fluid and salt in the diet (as long as their is no hypertension or heart failure), using compression stockings to improve venous return, addition of fludrocortisone to mimimise symptoms in those individuals with sufficient salt intake, midodrine to cause vasoconstriction and non-selective beta-blocker Propranolol which leads to uninhibited alpha-vasoconstrictive effects.

Lessons to be Learned

Avoid cranial scanning unless it is absolutely necessary; just because you can scan someone does not mean that you have to or that you should. A thorough history and examination may be sufficient to give all the necessary information. Only if there is a neurological abnormality e.g. upper motor neurone signs, should the patient be scanned.

Patients with a history of postural related symptoms should have a bedside measurement of blood pressure. An initial lying blood pressure should be performed and then repeating the measurements at 1, 2 and 3 minutes in the sitting position (if the patient cannot stand) or standing. If the patient is stood up, they should be supported in case of potential collapse with full resuscitation equipment being available. Blood pressure measurements should then be performed at 1, 2 and 3 minutes.

A blood pressure drop of more than 20 mmHg of the systolic and / or 10 mmHg of the diastolic (20/10 mmHg) is consistent with the diagnosis of postural hypotension.

In this case, there was a hint of dropping blood pressure at 3 minutes when sitting and this was confirmed after just 1 minutes of standing.

Patients without a supportive drug history and in whom there is no clear cut cause, should have a rectal examination to check for gastrointestinal haemorrhage. Consider other potential causes in the elderly as listed above.

This case is somewhat difficult and has a wide set of differential diagnoses. The fact that the patient had a fever for 6 weeks and he did not respond to antibiotic treatment makes a simple infection unlikely. The fact that the patient was reviewed several times at a clinic, and one would hope that basic investigations were performed, makes this a likely Fever of Unknown Origin (FUO)

Tuberculosis (this would not explain the neurological symptoms). If this patient had been living in a high risk area for leprosy (mycobacterium leprae), it might explain the neuropathy but not the cough and chest pain.

Viral

Parvovirus B19 can cause an upper respiratory infection, constitutional symptoms and joint involvement but cannot explain the neurological impairment. Other viruses that are

In this case, the patient underwent several tests. On admission, his haemoglobin was 8.1 with a normal MCV. BUN and Creatinine were abnormal at 28.5 and 1.4 respectively with normal sodium and potassium levels. Liver function was normal.

In view of the chest pain and raised calcium, an isotope bone scan was performed which shows some ‘hot spots’ at the costochondral junctions. The pelvic views show increased uptake at the sacroiliac joints suggesting a possible sacroiliitis.

MRI scan of the lower vertebral column revealed no metastatic disease or any area consistent with multiple myeloma.

This patient had non-specific symptoms of malaise, fatigue and appetite loss. The fact that both motor and sensory modalities were affected in one hand affecting the distribution of two peripheral nerves i.e. the ulnar and median nerves, makes one consider a distal motor-sensory polyneuropathy; with the addition of arthralgia makes a connective tissue disease much higher as the cause.

Wegener’s granulomatosis and microscopic polyangiitis would be regarded as the main two diagnoses here, as both can cause neuropathy and are associated with a rise in the serum ANCA. However, 90% of Wegener’s patients have PR3 ANCA versus 10% who have MPO ANCA positivity. The history of a non productive cough makes one consider Wegener’s Granulomatosis which affects both upper and lower respiratory tracts. However, there were none of the very classical upper respiratory features of the disease which can affect the nose, ear etc.

50% of patients with microscopic polyangiitis develop pulmonary disease and this is usually a pulmonary fibrosis.

The arthralgia is a non-specific symptom and can be present in infective, malignant and connective tissue disease but with the above history makes it more likely to be a connective tissue cause.

The majority of patients with microscopic polyangiitis have MPO-ANCA serum positivity and therefore, it was considered to be the most likely underlying diagnosis. Both Wegener’s Granulomatosis and Microscopic polyangiitis can cause renal impairment and hence, a renal biopsy was performed to investigate the underlying cause. The fact that the patient had no casts in the urine but high WBCs and RBCs plus bacteria suggested a UTI rather than a glomerulonephritis-- a lesson learned!

The fact that the patient had lateral leg pain with no joint or nerve stretch signs either suggests a localized myopathy, bone pain or a localized peripheral neuropathy such as a meralgia paraesthetica. However, the bone scan did not reveal bone uptake making a myopathy or neuropathy more likely.

The painful buttocks were likely to be a sacroiliitis as noted by the physical examination and the abnormal uptake in the sacroiliac joints on the bone scan. However, Xray of the sacroiliac joints revealed no obvious abnormality.

The renal biopsy showed: crescentic glomerulonephritis with 50% of the nephrons being involved. Immune staining was consistent with the diagnosis of microscopic polyangiitis.

Likely diagnosis: Microscopic Polyangiitis

Treatment with pulsed methylprednisolone was started and there was a dramatic drop in fever to the normal range with the patient feeling much better. However, the renal function deteriorated with a creatinine rise to over 3mg/dl in just one week prior to commencing this treatment. Moreover, despite pulse steroids, there was no immediate return of motor function in the affected upper extremity. This was not surprising in view of the prolonged duration it takes peripheral nerves to recover function. Electrophysiological studies were ordered to investigate the likely underlying inflammatory neuropathy.

The patient also underwent neck ultrasonography plus MIBG scanning of the neck.

The underlying diagnoses include:

1) Microscopic polyangiitis presenting with

Fever, malaise, fatigue and appetite loss

Motor-sensory polyneuropathy

Arthralgia

Possible meralgia paraesthetica

Anaemia of chronic disease

Crescentic glomerulonephritis

Positive MPO-ANCA

2) Primary Hyperparathyroidism presenting with

Hypercalcaemia

Bilateral rib pain and increased uptake on bone scan

Bilateral renal stones on ultrasound.

Mass in upper pole of right lobe of the thyroid

3) Sick Euthyroid state

Professor Masami Matsumura, Department of Internal Medicine, Kanazawa University Graduate School of Medicine, has again kindly answered the case.

His answer is frankly amazing and just from the history and examination!

"Thank you very much for showing challenging case! This case is difficult to diagnose, but challenging again.

This patient is previous healthy 61-year-old Japanese man. Patient first symptom was six-week history of cough. The patient thought that this was due to a common cold. Next fever appeared. From these information, I would point out possibilities of autoimmune, infection, and neoplastic diseases. Fatigue and malaise are not high yield symptoms. However, numbness and pain in the right hand, pain in the proximal lower limbs and buttock, and dragging of the left leg appeared. Mono-neuritis multiplex is highly suspected in this case. If physical examination showed findings of mono-neuritis multiplex, vasculitis is most likely.

Questions

1 From the history and physical examination, please make a problem list.

I listed problems as follows;

#1 Cough

#2 Fever

#3 Fatigue and Malaise

#4 Pain in the proximal lower limbs (L5, S1-2)

#5 Buttock pain (L5, S1-2)

#6 Dragging of the left leg

#7 Left sided weakness at age of 30 years

#8 Tachycardia

#9 Obesity, BMI 38.2

#10 Tenderness along the antero-lateral aspect of the ribs bilaterally.

#11 Reduced sensation and pain of the right hand (C6-8)

#12 Joint pain in the MCP joints of the index and middle finger, and several of the PIP joints, suspect polyarthritis

#13 Movements were reduced in extension and flexion of the fingers.

#14 Unable to grip paper between his thumb and index finger (pincer grip) or between the index and middle and the middle and ring finger (C8, T1)

#15 Pain over the sacro-iliac regions (L5, S1-2)

2 What are the possible differential diagnoses in this case?

This patient had cough, fever, and mono-neuritis multiplex.

Differential diagnoses are as follows. Dr. Tierney in SFVA taught this system. These eleven categories are great.

3 What tests would you undertake to investigate this patient's problem including both simple and advanced tests?

I highly suspect vasculitis in this case. In Japan, microscopic polyangiitis is not so rare. Wegener’s glanulomatosis is very rare in Japan. Churg-Strauss syndrome is also rare in any countries. Moreover, this patient doesn’t have history of asthma. Microscopic polyangiitis will involve lung and kidney. Measurement of creatinine, urinalysis, and chest x-ray are essential.

I think the above case and the expert breakdown into the essential elements by Professor Matsumura teaches us important lessons.

For example, autoimmune disease can present with motor-sensory weakness and moreover, a vasculitis can simulate what would initially appear to be a UTI !

As a matter of evidence based treatment, many patients with microscopic polyangiitis require both high dose steroids plus cyclophosphamide in order to settle the inflammation rather than just steroids alone.